title: Inhibition of mTORC1 by SU6656, the selective Src kinase inhibitor, is not accompanied by activation of Akt/PKB signalling in melanoma cells.
abstract: The mammalian target of rapamycin (mTOR) is a Ser/Thr protein kinase conserved in all eukaryotes that plays a key role in cell growth and is a central effector of several pathways regulating essential cell functions. Hyperactivation of the mTORdependent signalling pathway occurs in many human diseases and may be a selective target for their therapy. However, the dual nature of mTOR, existing in two multiprotein complexes mTORC1 and mTORC2 driven by different feedback loops, decreases the therapeutic effects of rapamycin, the specific mTOR inhibitor. In the present study we demonstrate that the mTORC1 signalling pathway is highly activated in human melanoma cells and that up-regulation of this pathway along with the growth and malignity of these cells could be suppressed by disruption of the Src activity. SU6656, the selective inhibitor of the Src kinase activity, decreased up-regulation of the mTORC1 signalling and moreover, unlike rapamycin, it did not induce the activation of Akt/PKB and its downstream targets in HBL melanoma cells. The Src protein was found to be associated with raptor in the mTORC1 complex immunoprecipitated from these cells, suggesting that the Src activity might be a new attractive target for monotherapeutic inhibition of the up-regulated mTORC1 signalling pathway.
authors.affiliation: Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic.
authors.forename: L
authors.initials: L
authors.lastname: Ondrušová
authors.forename: J
authors.initials: J
authors.lastname: Réda
authors.forename: P
authors.initials: P
authors.lastname: Záková
authors.forename: Z
authors.initials: Z
authors.lastname: Tuháčková
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007211:Indoles; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; C416927:SU 6656; D013449:Sulfonamides; D019061:src-Family Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus